The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance.

Autor:	Garton FC; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia., Houweling PJ; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia., Vukcevic D; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; School of Mathematics and Statistics, Faculty of Science, University of Melbourne, Parkville, VIC 3052, Australia; School of BioSciences, Faculty of Science, University of Melbourne, Parkville, VIC 3052, Australia; Centre for Systems Genomics, University of Melbourne, Parkville, VIC 3052, Australia., Meehan LR; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia., Lee FXZ; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, NSW 2145, Australia., Lek M; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA., Roeszler KN; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia., Hogarth MW; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia., Tiong CF; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia., Zannino D; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia., Yang N; Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia., Leslie S; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; School of Mathematics and Statistics, Faculty of Science, University of Melbourne, Parkville, VIC 3052, Australia; School of BioSciences, Faculty of Science, University of Melbourne, Parkville, VIC 3052, Australia; Centre for Systems Genomics, University of Melbourne, Parkville, VIC 3052, Australia., Gregorevic P; Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia., Head SI; School of Medical Sciences, University of New South Wales, Sydney, NSW 2031, Australia; School of Medicine, Western Sydney University, Sydney, NSW 2751, Australia., Seto JT; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia., North KN; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC 3052, Australia. Electronic address: kathryn.north@mcri.edu.au.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2018 May 03; Vol. 102 (5), pp. 845-857. Date of Electronic Publication: 2018 Apr 26.
DOI:	10.1016/j.ajhg.2018.03.009
Abstrakt:	Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta-analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3-1.6) but substantial heterogeneity in heterozygotes. In mouse muscle, rAAV-mediated gene transfer overexpressed and rescued α-actinin-3 expression. Contrary to expectation, in vivo "doping" of ACTN3 at low to moderate doses demonstrated an absence of any change in function. At high doses, ACTN3 is toxic and detrimental to force generation, to demonstrate gene doping with supposedly performance-enhancing isoforms of sarcomeric proteins can be detrimental for muscle function. Restoration of α-actinin-3 did not enhance muscle mass but highlighted the primary role of α-actinin-3 in modulating muscle metabolism with altered fatiguability. This is the first study to express a Z-disk protein in healthy skeletal muscle and measure the in vivo effect. The sensitive balance of the sarcomeric proteins and muscle function has relevant implications in areas of gene doping in performance and therapy for neuromuscular disease. (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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